Systems Biology Approaches to Study the Molecular Effects of Caloric Restriction and Polyphenols on Aging Processes
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Genes Nutr (2015) 10:58 DOI 10.1007/s12263-015-0508-9 RESEARCH PAPER Systems biology approaches to study the molecular effects of caloric restriction and polyphenols on aging processes 1 1 1 1 Se´bastien Lacroix • Mario Lauria • Marie-Pier Scott-Boyer • Luca Marchetti • 1,2 1 Corrado Priami • Laura Caberlotto Received: 17 February 2015 / Accepted: 13 November 2015 / Published online: 25 November 2015 Ó Springer-Verlag Berlin Heidelberg 2015 Abstract Worldwide population is aging, and a large part some examples on how to extend the application of these of the growing burden associated with age-related condi- methods using available microarray data. tions can be prevented or delayed by promoting healthy lifestyle and normalizing metabolic risk factors. However, Keywords Network analysis Á Multi-omics integration Á a better understanding of the pleiotropic effects of available Glutamate receptors Á Oxidative stress Á Inflammation Á nutritional interventions and their influence on the multiple Healthy aging processes affected by aging is needed to select and implement the most promising actions. New methods of analysis are required to tackle the complexity of the The molecular basis of nutritional strategies interplay between nutritional interventions and aging, and to promote healthy aging to make sense of a growing amount of -omics data being produced for this purpose. In this paper, we review how Global life expectancy and proportion of people aged over various systems biology-inspired methods of analysis can 60 years are increasing. Aging-associated comorbidities be applied to the study of the molecular basis of nutritional will become the next global public health challenge in the interventions promoting healthy aging, notably caloric context of westernization of daily habits and rising preva- restriction and polyphenol supplementation. We specifi- lence of risk factors for non-communicable chronic dis- cally focus on the role that different versions of network eases. This situation is thus calling for prophylactic analysis, molecular signature identification and multi- strategies to promote healthy aging (Suzman et al. 2015). omics data integration are playing in elucidating the Aging is characterized by a progressive appearance of complex mechanisms underlying nutrition, and provide various dysfunctions that lead to physical and metabolic frailty, which increase the risk of developing various dis- eases (Lee et al. 2011). Notably, antioxidant and anti-in- This article is part of a Topical Collection in Genes and Nutrition on flammatory capacity are affected with increasing age as is ‘‘Systems Nutrition and Health’’, guest edited by Jim Kaput, Martin Kussmann and Marijana Radonjic. the release and accumulation of stressors which result in a state of chronic low-grade inflammation and oxidative Electronic supplementary material The online version of this stress conceptualized, respectively, as ‘‘inflamm-aging’’ article (doi:10.1007/s12263-015-0508-9) contains supplementary material, which is available to authorized users. and ‘‘the free radical theory of aging’’ (Rubinsztein et al. 2011; Baylis et al. 2013; Beekman et al. 2013; Cevenini & Laura Caberlotto et al. 2013; Castellani et al. 2015). Another hallmark of [email protected] aging is the progressive decline of the autophagy process, which normally plays a protective, anti-cytotoxic role by 1 The Microsoft Research, University of Trento Centre for Computational Systems Biology (COSBI), Piazza degrading protein aggregates and dysfunctional cellular Manifattura 1, 38068 Rovereto, Italy components including mitochondria (Rubinsztein et al. 2 Department of Mathematics, University of Trento, 2011). By doing so, autophagy prevents the release of pro- Via Sommarive 14, 38123 Povo, Italy oxidative and pro-inflammatory toxins, but also regulates 123 58 Page 2 of 10 Genes Nutr (2015) 10:58 inflammation by exerting a control over the NLRP3 mammalian models (Speakman and Mitchell 2011). It was inflammasome and interleukin 1b production (Rubinsztein postulated that CR benefits result from evolutionary et al. 2011). Protein synthesis rates are also decreased in mechanisms that halts cell division and energy-requiring the aging individuals, which, when combined with the functions under conditions of energy imbalance (Speakman often-inadequate physical activity and nutritional habits of and Mitchell 2011). The benefits of CR on slowing or this population, increases risk of sarcopenia with ensuing preventing age-related dysfunctions are the result of its metabolic dysfunctions (Beyer et al. 2012; Fabian et al. influence on the many systemic effectors previously men- 2012). tioned as being affected in aging. This is demonstrated by Age-related dysfunctions thus arise from several several studies which showed that CR (1) negatively reg- molecular systems that share central molecular effectors ulates the insulin-like growth factor (IGF-1)/insulin particularly in the sirtuin family (SIRTs, regulators of receptor substrate (IRS)/PI3k–Atk pathways, (2) activates cellular energy metabolism and mitochondrial biogenesis) SIRT family members, (3) activates AMPK (through and adenosine monophosphate-activated protein kinase decreased ATP/AMP ratio), (4) inhibits the mTOR path- (AMPK, central regulator of energy metabolism) and their way, (5) improves fatty acid metabolism (via CPT-1 and downstream targets (Salminen and Kaarniranta 2012; SREBP-1), (6) decreases the release of ROS and pro-in- Merksamer et al. 2013). Dysfunctions in those systems flammatory compounds and (7) modulates the expression principally result in decreased capacity to respond to of genes implicated in neuroprotection (Lee et al. 2000; stressors, to regulate mitochondrial function and energy Rubinsztein et al. 2011; Speakman and Mitchell 2011; Dai metabolism and, through their interaction with the mam- et al. 2014). malian target of rapamycin (mTOR), to impaired autop- These effectors have been shown to have organ-specific hagy mechanisms (Rubinsztein et al. 2011; Salminen and effects. They partially act in synergy to improve muscle Kaarniranta 2012; Merksamer et al. 2013). energy metabolism, prevent muscle loss and mitochondrial Altogether, these alterations affect energy homeostasis dysfunction in mice (Jang et al. 2012; Lin et al. 2014; Chen and increase the risk of pathologies that share common et al. 2015) and induce mitochondrial biogenesis in the inflammatory and oxidative basis such as obesity, insulin skeletal muscle (of human as well), the heart, the adipose resistance, type II diabetes and cardiovascular diseases tissue and the brain (Baur 2010). CR also activates (Ceriello et al. 2004; Scrivo et al. 2011; North and Sinclair autophagy (Rubinsztein et al. 2011; Speakman and 2012). In the aging brain, the excessive release of oxidative Mitchell 2011). In the aging rat brain, CR improved ketone and inflammatory mediators coupled with impaired body metabolism and blood flow, often impaired in neu- autophagy mechanisms result in microvascular dysfunc- rodegenerative disorders (Lin et al. 2015). CR also delayed tions, protein oxidation, lipid peroxidation and DNA neurodegeneration in aging mice through SIRT1 (Graff damage, which eventually lead to ischemic damages, et al. 2013), improved learning through PI3k/Akt pathway abnormal protein aggregation, neuronal inflammation and (Ma et al. 2014) and was demonstrated to attenuate amy- cell death common to a number of neurodegenerative dis- loid b neuropathology in aged mice with Alzheimer’s orders (Rubinsztein et al. 2011; Rege et al. 2014; Salminen disease (Wang et al. 2005). Finally, one of the few inves- and Paul 2014). Moreover, excessive oxidative stress alters tigation conducted in humans showed that a 3-month CR synaptic transmission and neuronal excitability, which intervention improved memory in the elderly (Witte et al. leads to structural damage of the central nervous system 2009). (CNS) and decline of cognitive functions (Rizzo et al. 2014; Salminen and Paul 2014). Calorie restriction mimetics: the case of polyphenols Caloric restriction Caloric restriction, however, benefits from being initiated early in life to yield the most positive effects on aging, The pathophysiological implications of aging are thus particularly neuroprotective effects and was rarely inves- broad and include multiple systems. Promotion of healthy tigated in human partly because it is often accompanied by aging should therefore similarly have multiple pleiotropic side effects that make it hardly sustainable in the long-term targets of action. Approaches aimed at improving lifestyle (Speakman and Mitchell 2011). Alternative interventions and dietary habits are part of those strategies that have that would mimic—at least partially—the molecular and large spectrum or action. Caloric restriction (CR), referring physiological benefits of CR are thus of interest (Speakman to 20–40 % reduction in habitual daily energy intake, is and Mitchell 2011). Intermittent CR (or intermittent fast- one such intervention that has largely been investigated ing) is one such alternative previously shown to decrease since it was first identified to have potentially life- oxidative stress levels and improve insulin sensitivity in increasing benefits in yeast and, more recently, in humans, but more research has yet to be done in this area 123 Genes Nutr (2015) 10:58 Page 3 of 10 58 (Wegman et al. 2015). Polyphenols—a class of antioxidant biology approaches (Corthesy-Theulaz et al. 2005). These phytochemicals mostly found in plant-derived